The kappa-opioid receptor (KOR) is a member of the opioid receptor family which binds the opioid peptide dynorphin as the primary endogenous ligand. KOR has a wide, yet distinct distribution in the brain, spinal cord, and in pain neurons. Recently, there have been significant advances in understanding the role of KOR in controlling cognition and emotion in addition to insights into its involvement in neurological diseases such as epilepsy and neuropathic pain. These pathologies share the common feature of disruption of the induction of neuroplasticity. While this is not a particularly novel idea in epilepsy, an emerging scheme in the field of psychiatric disorders is that diseases such as addition and depression also stem from disruption in normal synaptic physiology and aberrant neuroplasticity that ultimately lead to maladaptive learning. Kappa opioid receptors have recently been investigated for their therapeutic potential in the treatment of addiction (Hasebe K, Kawai K, Suzuki T, Kawamura K, Tanaka T, Narita M, Nagase H, Suzuki T (2004) “Possible pharmacotherapy of the opioid kappa receptor agonist for drug dependence” Annals of the New York Academy of Sciences 1025: 404-13), and evidence points towards dynorphin to be one of the body's natural addiction control mechanism (Frankel P S, Alburges M E, Bush L, Hanson G R, Kish S J (2008) “Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users” Neuropharmacology 55 (1): 41-6).
In experimental “addiction” models the kappa-opioid receptor has also been shown to influence stress-induced relapse to drug seeking behavior. For the drug dependent individual, risk of relapse is a major obstacle to becoming drug free. Recent reports demonstrated that KOR are required for stress-induced reinstatement of cocaine seeking (Beardsley P M, Howard J L, Shelton K L, Carroll F I (2005) “Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats” Psychopharmacology (Berl.) 183 (1): 118-26; Redila V A, Chavkin C (2008). “Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system” Psychopharmacology 200 (1): 59-70; Blum K, Braverman E R, Holder J M, Lubar J F, Monastra V J, Miller D, Lubar J O, Chen T J, Comings D E (2000) “Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors” Journal ofpsychoactive drugs 32 Suppl: i-iv, 1-112). It has also been reported that the dynorphin-Kappa opioid system is critical for stress-induced drug seeking. In animal models, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner (McLaughlin J P, Marton-Popovici M, Chavkin C. (2003) “Kappa opioid receptor antagonism and prodynophin gene disruption block stress-induced behavioral responses” The Journal of Neuroscience 23 (13): 5674-83; Mash, Deborah C. (2006) “Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system” Neuropsychopharmacology 31 (4): 787-94). These effects are likely caused by stress-induced drug craving that requires activation of the dynorphin-KOR system. Although seemingly paradoxical, it is well known that drug taking results in a change from homeostasis to allostasis.
It has been suggested that withdrawal-induced dysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking. The rewarding properties of the drug are altered, and it is clear kappa-opioid activation following stress increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of kappa-opioid receptors is likely due to multiple signaling mechanisms. The kappa-opioid receptors have marked effects on all types of addiction including alcohol and opiate abuse. Cocaine addiction, as well as addiction to alcohol or other drug, is a world wide problem that has serious social, mental, and physical consequences. While various forms of prevention and/or treatment of addiction have been attempted, there remains a need for an improvement. For example, small molecules have been used as drugs to decrease the physical and/or mental conditions associated with addiction.
It is now thought that dysphoric elements of stress contributed to the development of anxiety states and clinical depression. There is recent evidence to suggest that dysphoric components of stress are encoded by the dynorphin-KOR system (Land B B, Bruchas M R, Lemos J C, Xu M, Melief E J, Chavkin C (2008) “The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system” J Neurosci 28(2):407-414). It has been demonstrated that stress decreases BDNF expression, which in turn predisposes the individual to depressive mood. Acute pretreatment with high doses of norBNI has been shown to increase BDNF mRNA expression in the area of hippocampus and the amygdala (Zhang H, Shi Y G, Woods J H, Watson S J, Ko M C (2007) “Central kappa-opioid receptor mediated antidepressant-like effects of nor Binaltorphimine: behavioral and BDNF mRNA expression studies” Eur J Pharmacol 570(1-3):89-96; Duman R S, Monteggia L M (2006) “A neurotrophic model for stress-related mood disorders” Biol Psychiatry 59(12):1116-1127).
Several behavioral studies using KOR agonists/antagonists as well as knockout animals have demonstrated a potential role for the dynorphin-KOR system in analgesia of neuropathic pain. (Gaveriaux-Ruff C, Kieffer B L (2002) “Opioid receptor genes inactivated in mice: the highlights” Neuropeptides 36 (2-3): 62-71).
There is a body of evidence to suggest that dynorphin peptide and message expression is up-regulated in both epileptic humans and animal models of epilepsy, suggesting that the dynorphin-KOR system play a significant role in the disease. (Bausch S B, Esteb T M, Terman G W, Chavkin C (1998) “Administered and endogenously released kappa opioids decrease pilocarpine-induced seizures and seizure-induced histopathology” J Pharmacol Exp Ther 284(3): 1147-1155; de Lanerolle N C, Williamson A, Meredith C et al (1997) “Dynorphin and the kappa 1 ligand [3H] U69,593 binding in the human epileptogenic hippocampus” Epilepsy Res 28(3): 189-205; Loacker S, Sayyah M, Wittmann W, Herzog H, Schwarzer C (2007) “Endogenous dynorphin in epileptogenesis and epilepsy: anticonvulsant net effect via kappa opioid receptors” Brain 130(pt 4): 1017-1028; Houser C R, Miyashiro J E, Swartz B E, Walsh G O, Rich J R, Delgado-Escueta A V (1990) “Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy” J Neurosci 10(1):267-282; De Sarro G B, De Sarro A (1993) “Anticonvulsant properties of non-competitive antagonists of the N-methyl-D-aspartate receptor in genetically epilepsy-prone rats: comparison with CPPene” Neuropharmacology 32(1):51-58).
It has been suggested that the dynorphin-KOR system is involved in the learning process. A negative correlation between the level of spatial learning and the level of dinorphin immunoreactivity in the hippocampal formation has been demonstrated (Jiang H K, Owyang V V, Hong J S, Gallagher M (1989) “Elevated dynorphin in the hippocampal formation of aged rats: relation to cognitive impairment on a spatial learning task” Proc Natl Acad Sci USA 86(8):2948-2951). In humans, the brain of Alzheimer disease patients have significant increase in dynorphin expression compared to age matched controls (Mathieu-Kia A M, Fan L Q, Kreek M J, Simon E J, Hiller J M (2001) “Mu-, delta- and kappa-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer's disease patients” Brain Res 893(1-2): 121-134).